Forewing movements and motor activity during roll manoeuvers in flying desert locusts

Desert locusts, tethered on a roll torque meter and flying in a wind tunnel are surrounded by an artificial horizon (Fig. 1). Flight motor activity and movement of forewings are monitored continuously. Movements of the artificial horizon elicit roll manoeuvers of the animal with latencies of several seconds; concomitant changes in flight motor pattern and wing movement can be correlated with the animal's roll angle and roll torque. Flight sequences with constant torque and roll angle (steady state) have been analysed with the following results. Wing Kinematics. A phase difference between the movements of the forewings on either side is correlated with roll angle (Fig. 3). Pronation of a forewing is always greater on the side to which the animal rolls, i.e. on the side that produces less lift (Fig. 5). In some experiments the slope of the wing tip path is also decreased (Fig. 5). In both cases, the aerodynamic angle of attack is decreased and the forewing on this side produces less lift. In most experiments, changes in pronation are less pronounced in the contralateral wing (Fig. 11). All factors contribute to a net roll torque that sustains the animal's roll angle. Other kinematic parameters of forewing movement, e.g. wing stroke amplitude, were not found to be correlated with roll angle and torque (Fig. 4). Motor Pattern. Activity of several flight muscles (depressors M97, M98, M99, and M129; elevators M83, M84, and M90) was investigated for changes in burst length and temporal coordination in response to roll stimuli. Most flight muscles fired only once per wing beat cycle in our preparations. Thus, burst length was not found to be correlated with roll angle. Time intervals of firing between all muscle pairs investigated change in correlation with the torque and roll angle (Fig. 9).All mesothoracic muscles are active earlier-relative to the ipsilateral metathoracic subalar muscle M129-during roll to the ipsilateral side than during roll to the contralateral side. Correlations Between Motor and Movement Pattern. The phase of muscle firing within the wing beat cycle varies with roll angle (roll torque). The first basalar M97 and second tergosternal M84 muscles, when referenced e.g. to the upper (M97) or lower (M84) reversal point of the wing tip trajectory, are active earlier on the side the animal turns to (Fig. 10). The onset of the first basalar M97 relative to the beginning of downstroke is correlated with maximum pronation and roll angle (Fig. 11). Mechanisms of Lift Control. Wing pronation, which is very important for lift production is controlled by the central nervous system by altering the phase of muscle activity within the wing beat cycle.     

Therapy with monoclonal antibodies. An in vivo model for the assessment of therapeutic potential.

A set of rat-human and rat-rat chimeric mAb has been created, all possessing V regions identical in their specificity for the mouse CD8 Ag. In vitro all antibodies were able to block cell-mediated lysis but varied greatly in their capacity to utilize rabbit complement. We examined the ability of these chimeric antibodies to deplete in vivo and established a clear hierarchy. Of the human IgG subclasses, only IgG1, 2, and 3 could fix complement in vitro, yet all (IgG1-4) were remarkably potent at depleting CD8+ PBL in vivo. In contrast, human IgA2 and IgE were ineffective at clearing CD8+ PBL. The vector system used to create these antibodies together with the small doses of antibodies required to deplete in vivo make this a simple and rapid system for testing the effects of different antibody isotypes and mutants. We have shown that a mutant of human IgG1, which is incapable of fixing complement, depletes perfectly well in vivo, whereas an aglycosyl IgG1 mutant is rendered inactive. Our model provides a unique opportunity to study effector functions and motifs that are used by mAb in vivo and will help in the design of improved antibodies for human therapy.     

North American Blastomycosis in California—Diagnosis of a Case and a Survey with 28 California Observed Cases

North American blastomycosis is not seen often in California. An exhaustive survey uncovered records of only 28 cases. It is believed that this disease does not occur naturally in California and that a careful study of the history will reveal that a residence or visit to a known endemic area can be found.A chart summarizing the results of complement fixation and skin tests for coccidioidomycosis, North American blastomycosis, and histoplasmosis in the 28 cases is included. Use of all three antigens is recommended in cases where there is a difficult diagnostic pulmonary problem, even though there is occasional occurrence of cross-reactions between the three antigens. Finally, an appeal is made to be aware of other mycotic diseases non-edemic to this state.     

Using small molecules to target protein phosphatases

The site specific functionalization of phosphate groups with amino acid side chains of substrate proteins represents one of the most important regulatory mechanisms of biological systems. Phosphorylation and dephosphorylation are reversibly catalyzed by protein kinases and protein phosphatases, and the aberrant regulation of these enzymes is associated with the onset and progression of various disease states such as cancer, diabetes, neurodegenerative and autoimmune disorders, making these proteins attractive targets for drug discovery. Here we report on strategies currently explored for the identification and development of various inhibitors directed against clinically relevant phosphatases. While over the last years, inhibition of phosphorylation has evolved into a key strategy in targeted therapies, the development of clinically relevant phosphatase inhibitors still faces major bottlenecks and is often plagued by limited selectivity and unfavorable pharmacokinetics. The reader will gain a better understanding of the importance of the field and its current limitations.     

Control of vertebrate multiciliogenesis by miR-449 through direct repression of the Delta/Notch pathway

Multiciliated cells lining the surface of some vertebrate epithelia are essential for various physiological processes, such as airway cleansing. However, the mechanisms governing motile cilia biosynthesis remain poorly elucidated. We identify miR-449 microRNAs as evolutionarily conserved key regulators of vertebrate multiciliogenesis. In human airway epithelium and Xenopus laevis embryonic epidermis, miR-449 microRNAs strongly accumulated in multiciliated cells. In both models, we show that miR-449 microRNAs promote centriole multiplication and multiciliogenesis by directly repressing the Delta/Notch pathway. We established Notch1 and its ligand Delta-like 1(DLL1) as miR-449 bona fide targets. Human DLL1 and NOTCH1 protein levels were lower in multiciliated cells than in surrounding cells, decreased after miR-449 overexpression and increased after miR-449 inhibition. In frog, miR-449 silencing led to increased Dll1 expression. Consistently, overexpression of Dll1 mRNA lacking miR-449 target sites repressed multiciliogenesis, whereas both Dll1 and Notch1 knockdown rescued multiciliogenesis in miR-449-deficient cells. Antisense-mediated protection of miR-449-binding sites of endogenous human Notch1 or frog Dll1 strongly repressed multiciliogenesis. Our results unravel a conserved mechanism whereby Notch signalling must undergo miR-449-mediated inhibition to permit differentiation of ciliated cell progenitors.     

A role for interleukin-2 trans-presentation in dendritic cell-mediated T cell activation in humans, as revealed by daclizumab therapy

Although previous studies have described CD25 expression and production of interleukin-2 (IL-2) by mature dendritic cells (mDCs), it remains unclear how these molecules participate in the activation of T cells. In search of the mechanisms by which daclizumab, a humanized monoclonal antibody against CD25, inhibits brain inflammation in multiple sclerosis, we observed that although the drug has limited effects on polyclonal T cell activation, it potently inhibits activation of antigen-specific T cells by mDCs. We show that mDCs (and antigen-experienced T cells) secrete IL-2 toward the mDC-T cell interface in an antigen-specific manner, and mDCs 'lend' their CD25 to primed T cells in trans to facilitate early high-affinity IL-2 signaling, which is crucial for subsequent T cell expansion and development of antigen-specific effectors. Our data reveal a previously unknown mechanism for the IL-2 receptor system in DC-mediated activation of T cells.